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Category: genetics

A novel mechanism for cancer-associated weight loss

Combined metabolomics and transcriptomics analysis in eight different organs of tumor-bearing mice with and without cachexia allowed researchers to create metabolic signatures typical of cancer-associated weight loss. High-throughput analyses identified a cachexia-specific metabolic and genetic signature that provides insight into the progression of these metabolic changes.

The researchers found that all organs showed increased activation of the so-called “one carbon cycle”, a biochemical process essential for the synthesis of nucleotides, amino acids, and cell regeneration. Products of this cycle, such as sarcosine or dimethylglycine, could potentially serve as biomarkers for cachexia in the future.

The study also revealed that hyperactivation of the one carbon cycle in muscle is associated with increased glucose metabolism (glucose hypermetabolism) and muscle atrophy. Early experiments suggest that inhibiting this process could prevent muscle loss. Comparative analyses across eight different mouse tumor models (lung, colon, and pancreatic cancer) confirmed that the one carbon signature represents a universal cachexia signature, independent of cancer type.

Currently, there is no approved drug for cancer cachexia in Germany. New approaches are being explored to address cancer-related appetite loss. This study provides the first evidence of how metabolism itself could potentially be normalized. Early experiments in cell cultures show that interventions targeting the one carbon cycle can have positive effects. sciencenewshighlights ScienceMission.

Cachexia is a metabolic disorder that causes uncontrolled weight loss and muscle wasting in chronic diseases and cancer. A new study shows that cachexia affects more than just muscles. Numerous organs respond in a coordinated manner, ultimately contributing to muscle loss. Analysis of metabolome and transcriptome data, along with glucose tracing in tumor-bearing mouse models, identified a novel mechanism that plays a key role in cancer-associated weight loss.

A loss of 10% of body weight within six months – what may sound desirable in some contexts – often causes uncertainty and frustration in cancer patients with cachexia, as they are unable to maintain or gain body weight despite wanting to. Cachexia (from the Greek kakós, “bad,” and héxis, “condition”) affects 50–80% of all cancer patients, reduces quality of life, diminishes the effectiveness of cancer therapies, and increases mortality.

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Targeting CDK2 for cancer therapy

How CDK2 inhibitors halt cancer cell division👇

✅G1 arrest in p16INK4A-high, cyclin E–high tumors (A, left). In tumors with high p16INK4A and cyclin E, catalytic CDK2 inhibitors block phosphorylation of key CDK2 substrates, including RB and nucleolin, and reduce signals from CDK activity sensors. This suppresses E2F transcriptional activity, leading to reduced cyclin A expression and failure to enter S phase. The net result is a G1 cell-cycle arrest, driven by effective shutdown of the RB–E2F axis.

✅4N accumulation when p16INK4A is absent (A, right). In tumors lacking p16INK4A, CDK2 catalytic inhibition alone does not efficiently block RB phosphorylation or early G1 molecular events. Instead, cells continue through S phase and accumulate with 4N DNA content, indicating arrest later in the cycle (post-replication). In this context, adding a CDK4/6 inhibitor can mimic the p16INK4A state, restore RB dephosphorylation, repress E2F, and shift cells toward a G1 arrest, highlighting the importance of dual CDK control of RB.

✅Catalytic inhibition vs genetic depletion of CDK2 (B). Genetic loss of CDK2 is often tolerated because cells can compensate using cyclin A–CDK1 to complete G2/M. In contrast, catalytic CDK2 inhibitors trap CDK2 in inactive complexes with cyclins, which may interfere with normal handoff to CDK1 and other cell-cycle processes. This leads to accumulation of cells with 4N DNA content, reflecting a block after DNA replication.

✅Why the outcomes differ. These findings suggest that CDK2 has roles beyond simple kinase activity—its inactive, cyclin-bound state under catalytic inhibition may disrupt network dynamics differently than complete protein loss. The precise mechanisms of the 4N arrest are still being investigated and may involve defects in S/G2 transitions, replication stress responses, or mitotic entry control.

✅Therapeutic implication. Tumor response to CDK2 inhibitors depends strongly on p16INK4A status, cyclin E levels, and RB pathway integrity. This supports combination strategies (CDK2 + CDK4/6 inhibition) in selected cancers and emphasizes the need for biomarker-guided patient stratification.

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A new atlas could help guide researchers studying neurological disease

Functioning brain cells need a functioning system for picking up the trash and sorting the recycling. But when the cellular sanitation machines responsible for those tasks, called lysosomes, break down or get overwhelmed, it can increase the risk of Alzheimer’s, Parkinson’s, and other neurological disorders.

“Lysosomal function is essential for brain health, and mutations in lysosomal genes are risk factors for neurodegenerative diseases,” said Monther Abu-Remaileh, a Wu Tsai Neuro affiliate and an assistant professor of chemical engineering in the Stanford School of Engineering and an assistant professor of genetics in the Stanford School of Medicine.

The trouble is, scientists aren’t sure exactly how lysosomes do their work, what’s going wrong with lysosomes that leads to neurodegeneration—or even in which cell types neurodegenerative disease begins. There might even be other lysosomal disorders yet to be discovered.

Making Hidden States Visible

Experiments with programmable electroacoustic cavities reveal that a multistable system can be steered into states that are unreachable with conventional control methods.

Many physical systems can be in more than one stable state: A laser can be on or off, and a magnetic bit up or down. This multistability can appear in nonlinear resonators—such as ferromagnets and genetic toggle switches in cells—that are driven into different steady states, or “branches,” by ramping up and down the driving parameter [1]. This behavior is often pictured using a familiar hysteresis loop that traces the system’s trajectory between a lower branch and higher branch (Fig. 1). It is easy to imagine that additional steady states might coexist with those sampled, but experiments have largely ignored that possibility, assuming instead that slow, quasistatic parameter sweeps reveal all “physically relevant” behavior.

In a new acoustic experiment, Kun Zhang from the Wuhan University in China and colleagues challenge that assumption [2]. They show that a pair of coupled acoustic cavities can host a fully “folded” steady state that is perfectly stable yet invisible to conventional sweeps. This hidden branch can, however, be reached with carefully designed sound pulses, the team shows. These results—combined with those from another recent study [3]—turn the abstract idea of hidden multistability into a concrete and controllable feature of nonlinear resonator networks, which might one day be used to securely store sensitive information.

Air Pollution Linked to Higher ALS Risk And Faster Decline

The scientist Stephen Hawking lived with amyotrophic lateral sclerosis (ALS), the most common type of motor neurone disease, for 55 years. He was one of the longest-surviving people with the condition.

However, most people with motor neurone disease are not as lucky. It often progresses quickly, and many pass away within two to five years of diagnosis.

There is still no cure. Genetics account for only about 10% of cases, and the rest of the causes are still largely a mystery.

APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition

APOE allele switching improves Alzheimer’s in mice.

Type of apolipoprotein E (APOE) allele carried by individuals is a major risk factor in Alzheimer’s disease (AD). For example, compared to individuals carrying two copies of the APOE ε4 allele, ε2 homozygotes have an approximate 99% reduction in late-onset Alzheimer’s disease (AD) risk.

The authors in this study developed a knock-in mouse model that allows for an inducible ‘switch’ between risk and protective alleles (APOE4s2). These mice synthesize E4 at baseline and E2 after tamoxifen administration.

A whole-body allelic switch resulted in a metabolic profile resembling E2/E2 humans and drives AD-relevant alterations in the lipidome and single-cell transcriptome, particularly in astrocytes.

E4 to E2 switching improved cognition, decreased amyloid pathology, lowered gliosis and reduced plaque-associated apolipoprotein E.

Thus, APOE replacement may be a viable strategy for future gene editing approaches to simultaneously reduce multiple AD-associated pathologies. sciencenewshighlights ScienceMission https://sciencemission.com/APOE4-to-APOE2-allelic-switching

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Specialized transporters relay lipids to cellular targets

In addition to providing energy, lipids are also essential building blocks of our cell membranes. However, despite their importance, they remain poorly understood. A research team has revealed for the first time the secrets of their transport within cells. Each lipid uses a limited number of proteins to move from its place of production to its place of action. The team has also compiled an inventory of the proteins involved in the transport of hundreds of lipids.

These findings, published in the journal Nature, provide a better picture of the functioning of our cells, as well as of many genetic and metabolic disorders, such as diabetes and Alzheimer’s disease.

Biologists brought together more than a hundred transfer proteins with hundreds of different lipids. The aim was to obtain the most comprehensive list possible of the ‘pairs’ formed between each protein and the lipids it can carry.

To do this, two experimental methods were combined. The first, carried out in a test tube, provides a highly controlled environment, while the second, which more closely corresponds to the inside of a cell, allows researchers to verify how these bonds are formed under near-real conditions. This is a world first on such a scale and at such a level of complexity. “The ‘‘couples’’ identified show that transfer proteins are not “buses” capable of transporting most lipids, but private chauffeurs with specific characteristics,” explains the senior author.

Scientists have been able to determine, using advanced mathematical models, how three transfer proteins recognise, among all lipids, those that they actually transport. ScienceMission sciencenewshighlights.

Scientists identify promising new target for Alzheimer’s-linked brain inflammation

A multidisciplinary team has developed a selective compound that inhibits an enzyme tied to inflammation in people at genetic risk for Alzheimer’s, while preserving normal brain function and crossing the blood-brain barrier.

The findings are published in the journal npj Drug Discovery.

The driver is an enzyme called calcium-dependent phospholipase A2 (cPLA2). The team discovered its role in brain inflammation by studying people who carry the APOE4 gene —the strongest genetic risk factor for Alzheimer’s disease. While many people who have the APOE4 gene don’t develop the disease, those with elevated levels of cPLA2 generally do.

How beige fat keeps blood pressure in check

In this report, researchers link thermogenic adipose tissue (brown/beige fat), best known for heat production, to blood-pressure control via direct fat–blood vessel communication. Using mouse models engineered to lose beige fat identity (via adipocyte-specific disruption of PRDM16), they observed elevated arterial pressure alongside perivascular remodeling, including fibrotic tissue accumulation and marked vascular hypersensitivity to the vasoconstrictor hormone angiotensin II. Mechanistically, loss of beige fat identity increased secretion of QSOX1 (quiescin sulfhydryl oxidase 1), which activated pro-fibrotic gene programs in vascular cells and promoted vessel stiffening; blocking this pathway (including genetic removal of QSOX1 in the model) restored healthier vascular signaling and function. The authors characterize this as a previously underappreciated, obesity-independent axis by which the “quality” (thermogenic vs white-like) of perivascular fat influences vascular stiffness and responsiveness to pressor signals, suggesting QSOX1 and related adipose-derived signals as potential precision targets for future antihypertensive therapies.

A mouse aorta with immunofluorescent tagging, emphasizing the close connection between vasculature and fat. (Credit: Cohen lab)

Obesity causes hypertension. Hypertension causes cardiovascular disease. And cardiovascular disease is the leading cause of death worldwide. While the link between fat and high blood pressure is clearly central to this deadly chain, its biological basis long remained unclear. What is it about fat that impacts vascular function and blood pressure control?

Now, a new study demonstrates how thermogenic beige fat—a type of adipose tissue, distinct from white fat, that helps the body burn energy—directly shapes blood pressure control. Building on clinical evidence that people with brown fat have lower odds of hypertension, the researchers created mouse models that cannot form beige fat (the thermogenic fat depot in mice that most closely resembles adult human brown fat) to watch what happens when this tissue is lost. They found that the loss of beige fat increases the sensitivity of blood vessels to one of the most important vasoconstricting hormones (angiotensin II)—and that blocking an enzyme involved in stiffening vessels and disrupting normal signaling can restore healthy vascular function in mice. These results, published in Science (opens in new window), reveal a previously unknown mechanism driving high blood pressure and point toward more precise therapies that target communication between fat and blood vessels.

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